P662: POST HOC ANALYSIS OF PATIENT RESPONSES BY T315I MUTATION STATUS FROM THE 3-YEAR UPDATE OF THE OPTIC TRIAL: A DOSE-OPTIMIZATION STUDY OF 3 STARTING DOSES OF PONATINIB
Authors: Jorge Cortes, Michael Deininger, Elza Lomaia, Beatriz Moiraghi, Soledad Undurraga, Carolina Pavlovsky, Charles Chuah, Tomasz Sacha, Jeffrey H. Lipton, James Mccloskey, Philippe Rousselot, Gianantonio Rosti, Hugues de Lavallade, Christine Rojas, Anna Turkina, Moshe Talpaz, Michael Mauro, Vickie Lu, Alexander Vorog, Jane Apperley
Journal: HemaSphere (2023)

Topic: 8. Chronic myeloid leukemia - Clinical Background: Ponatinib is the only pan-BCR::ABL1 inhibitory tyrosine kinase inhibitor (TKI) designed to potently inhibit native and all single resistance–mutation variants of BCR::ABL1, including T315I. Patients with T315I BCR::ABL1 mutations respond inadequately to earlier-generation BCR::ABL1 TKIs, leading to poor survival outcomes. OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270) is a Phase 2 trial evaluating the efficacy and safety of ponatinib using a novel response-based dose-adjustment strategy in patients with chronic-phase chronic myeloid leukemia (CP-CML) whose disease is resistant to ≥2 TKIs or who harbor the T315I mutation. Aims: Here we present a post hoc analysis of the 3-year OPTIC trial patient responses by T315I mutation status. Methods: Patients with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mutation were randomized to ponatinib starting doses of 45, 30, or 15 mg once daily. In the 45-mg and 30-mg cohorts, doses were reduced to 15 mg with achievement of ≤1% BCR::ABL1IS. The primary endpoint was ≤1% BCR::ABL1IS at 12 months; secondary endpoints included molecular responses and safety outcomes. Progression-free survival (PFS) and overall survival (OS) probabilities by 36 months were estimated using the Kaplan-Meier methodology. Here we analyzed outcomes by baseline T315I mutation status. BCR::ABL1 mutations were assessed by Sanger sequencing. Results: Overall, 282 patients (99% resistant) received ponatinib (45 mg/30 mg/15 mg: n=94/94/94); 23.4% had the T315I mutation. In patients with no mutation, the T315I mutation, and mutation other than T315I, the highest percentage of patients achieving ≤1% BCR::ABL1IS by 36 months was in the 45-mg cohort: 60%, 64%, and 56%, respectively (Table). In patients with the T315I mutation, 32% (8/25) and 10% (2/20) in the 45-mg and 30-mg cohorts had their dose re-escalated after loss of response; of these patients, 75% and 50% re-achieved ≤1% BCR::ABLIS, respectively. In patients with no mutation, 6% (3/50) and 5% (3/58) in the 45-mg and 30-mg cohorts had their dose re-escalated after loss of response; of these patients, 67% and 100% re-achieved ≤1% BCR::ABLIS, respectively. In patients with a mutation other than T315I, 12.5% (2/16) in the 45-mg cohort had their dose re-escalated after loss of response and 50% (1/2) of these patients re-achieved ≤1% BCR::ABLIS; no patients in the 30-mg cohort lost response. Among patients with the T315I mutation, the 45-mg cohort had a higher 3-year PFS rate (75%) than the 30-mg (40%) or 15-mg (61%) cohorts; the 3-year OS rate was similar in the 45-mg (86%) and 15-mg (85%) cohorts (Table). Most-common Grade ≥3 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and anemia (8%). Incidences of Grade 3–4 arterial occlusive events (AOEs) in the 45-, 30-, and 15-mg cohorts were 6%, 6%, and 4%, respectively; there were no Grade 5 AOEs. Summary/Conclusion: This post hoc analysis from the 3-year update of the OPTIC trial demonstrated robust long-term efficacy of ponatinib and manageable safety across mutation subgroups. A ponatinib starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS provided the optimal benefit:risk ratio regardless of mutation status, which is consistent with the results from the primary analysis.Keywords: Chronic myeloid leukemia